Mosaicism and Linear Lesions

Introduction

Incontinentia pigmenti (IP) is a multisystem disorder with an estimated birth prevalence of 1 : 140 000 and a female : male ratio of ~20 : 1. Patients may present to neonatologists, neurologists, ophthalmologists, or dentists as well as dermatologists. However, the diagnosis rests on the cutaneous findings. The name refers to the pathologic finding of pigmentary incontinence, i.e. dermal melanophages, in the third stage of the disease. The linear skin lesions reflect mosaicism secondary to X inactivation (lyonization).

History

Although Garrod probably first described IP in 1906, Bloch's 1926 report of a “previously unreported pigment disorder” and that 2 years later by Sulzberger are remembered eponymously. In 2000, the International Incontinentia Pigmenti Consortium established that IP is caused by mutations in IKBKG which encodes inhibitor of κ light polypeptide gene enhancer in B cells, kinase γ, also known as NEMO ( N F-κB e ssential mo dulator). A separate condition previously known as “IP1” is now recognized as a form of pigmentary mosaicism (see below).

Genetics

IP is an X-linked dominant disorder, usually antenatally lethal in boys, that is caused by mutations in IKBKG located at Xq28 . Approximately two-thirds of patients have a common large deletion of exons 4–10 that tends to arise during paternal meiosis (male gametogenesis). Occasional occurrences of clinically typical IP in boys are attributed to Klinefelter syndrome (~10% of male patients) or to genomic mosaicism due to a half-chromatid or postzygotic NEMO mutation ( Table 62.5 ) . In the latter patients, the distribution of the skin lesions may be relatively limited.

Pathogenesis

The NEMO protein is a subunit of a kinase that activates NF-κB, a transcription factor that protects against TNF-α-induced apoptosis ( Fig. 62.4 ). The idea of IP as a pro-apoptotic state explains male lethality, destruction of epidermal cells, and progressive replacement of cells expressing the mutant X chromosome by those expressing the normal allele . In one report, a liveborn boy whose mother had classic IP died hours after birth due to lethal hematopoietic and immunologic disturbances . Milder hypomorphic NEMO mutations are responsible for hypohidrotic ectodermal dysplasia with immune deficiency (HED-ID) in boys, whose mothers often have relatively subtle features of IP (see Table 62.5 and Ch. 63 ) .

Clinical features

IP typically presents with linear erythema and vesicles (stage 1) during the first few weeks to months of life in an otherwise healthy baby girl (see Fig. 34.13 ) . Vesiculobullous lesions are most common on the limbs and scalp, frequent on the trunk, and rare on the face ( Fig. 62.5A ). They resolve within days to weeks and are often replaced by verrucous linear plaques (stage 2) that favor the extremities ( Fig. 62.5B ) and usually disappear later in infancy. Streaks and swirls of reticulate grayish-brown hyperpigmentation (stage 3) develop next and have a predilection for the trunk and intertriginous sites, with scalloped edges that are thought to reflect the growth of normal keratinocytes into affected skin ( Fig. 62.5B, C ). The inflammatory sequence sometimes recurs within pigmented areas during later infancy or childhood together with intercurrent febrile illnesses. In addition, acral keratotic nodules (including subungual lesions) occasionally arise after puberty. The hyperpigmented streaks tend to fade by adolescence, although a few areas of slate-gray pigmentation may persist lifelong. From puberty onward, linear hypopigmented bands lacking hair and sweat glands (stage 4) appear on the posterior aspects of the limbs (especially the calves; Fig. 62.5D ) and may be the only stigmata of the disease during adulthood . Individual stages of IP may be absent or overlap. Extracutaneous manifestations of this condition are listed in Table 62.6 .

Pathology

The early inflammatory phase of IP demonstrates eosinophilic spongiosis and scattered dyskeratotic keratinocytes. The epidermis of verrucous lesions is acanthotic with hyperkeratosis and foci of dyskeratosis. In stage 3, there is pigmentary incontinence as well as variable vacuolization of basal keratinocytes, whereas stage 4 is characterized by a thinned epidermis and dermis devoid of adnexa .

Differential diagnosis

Neonatal IP can usually be distinguished from infectious conditions (e.g. herpes zoster, varicella, herpes simplex viral infections) by the wellbeing of the child and characteristic patterning of the skin lesions. Peripheral eosinophilia and leukocytosis are common in neonates with IP, and histologic examination can confirm the diagnosis. In linear nevoid hyper- or hypopigmentation, there is no preceding inflammatory phase, the hyperpigmentation is epidermal, and adnexa are typically normal.

Treatment

Baseline and longitudinal ophthalmologic (especially during infancy) and neurologic evaluations are recommended, as are dental assessments and early intervention when anomalies are present. The mother should be examined for subtle atrophic streaks, usually most visible on the calves, and genetic counseling provided. The Incontinentia Pigmenti International Foundation ( www.ipif.org ) is a good resource for families.

Introduction

This uncommon genetic disorder was first described by Goltz in 1962 and ectodermal and mesodermal structures – primarily the skin, eyes, teeth, and bones – are affected in a mosaic pattern.

Genetics

Goltz syndrome is an X-linked dominant condition caused by mutations in PORCN , with the mosaic distribution of skin lesions in female patients reflecting lyonization. Although Goltz syndrome is antenatally lethal in boys with non-mosaic hemizygous mutations (as in IP; see Table 62.5 ), male patients with genomic (e.g. due to a postzygotic mutation) or functional (in the setting of Klinefelter syndrome) mosaicism account for ~10% of affected individuals.

Approximately 95% of all Goltz syndrome cases are sporadic, which likely reflects both a decreased likelihood of reproduction by severely affected women and the lethality of PORCN mutations with widespread expression. Some authors have postulated that either preferential inactivation of the mutant X chromosome or a postzygotic mutation is required for survival of affected female fetuses . Rare familial cases often show anticipation, with the offspring being more severely affected than the parent and having a higher proportion of cells expressing the mutant X chromosome. The possibility that an apparently normal mother is a carrier must therefore be considered.

Pathogenesis

PORCN belongs to the evolutionarily conserved porcupine gene family and is expressed in the skin, craniofacial and long bones, tooth buds, and eyes – structures affected in Goltz syndrome. PORCN is an endoplasmic reticulum protein with multiple transmembrane domains. It functions as an O-acyltransferase involved in palmitoylation and secretion of Wnt, a morphogen important in ectomesodermal tissue development . Wnt signaling stimulates fibroblast proliferation, inhibits adipogenesis, and induces osteogenesis, explaining the dermal hypoplasia, fat “herniations”, and osteopathia striata (streaks of decreased bone density) observed in Goltz syndrome. Wnt also has key roles in early limb patterning and tooth formation.

Although the primary cutaneous abnormality in Goltz syndrome is in the dermis, the distribution of skin lesions along the lines of Blaschko reflects embryonic migration pathways of epidermal cells. Ectoderm-specific deletion of PORCN in mice has shown that expression of this gene in the epidermis and resultant Wnt signaling regulate development of the underlying dermis and fat . Of note, patients with Goltz syndrome have a thin epidermis and abnormal adnexal structures. This is not surprising considering that Wnt signaling, including β-catenin-dependent pathways, is known to have critical roles in epidermal regeneration and adnexal morphogenesis/maintenance (see Fig. 55.6 ).

In 3 of 24 patients in one series, a microdeletion affected both PORCN and the adjacent EBP gene responsible for Conradi–Hünermann–Happle syndrome (see below). Curiously, however, these patients showed no features of the latter disorder. This implies that the PORCN -related hypoplastic skin phenotype predominates over the ichthyosis and follicular changes of Conradi–Hünermann–Happle syndrome .

Clinical features

The phenotype of Goltz syndrome is highly variable, depending on the proportion and distribution of cells expressing the mutant X chromosome . Streaks of vermiculate dermal atrophy and/or telangiectasias are often present from birth ( Fig. 62.6A–C ). Later, hypo- and hyperpigmentation as well as “herniations” of fat develop. Although “raspberry-like” papillomas with a verrucous surface and fibrovascular core may appear in any location, they favor the anogenital region as well as the lips ( Fig. 62.6D ), larynx, and acral sites. Limb malformations affect >80% of patients and include ectrodactyly (split hand/foot malformation), asymmetric syndactyly, oligodactyly, and long bone reduction defects. Radiographs of the midportion of the lower extremities characteristically show osteopathia striata. Eye abnormalities, often unilateral, include iritic and chorioretinal colobomas, microphthalmia, anophthalmia, and cataracts. Dystrophic nails (e.g. longitudinal fissures, hypoplasia), sparse hair, abnormal teeth (e.g. vertical grooving, hypodontia), and dysmorphic facies (e.g. notched nasal alae, pointed chin, large malformed ears) may be observed. Other reported features include aplasia cutis congenita, ventral body wall defects, cleft lip/palate, gastrointestinal dysfunction, impaired hearing, intellectual impairment, and anomalies of the spine, urinary tract, or uterus.

Pathology

Affected skin shows a marked reduction in the thickness of the dermis, with fewer adnexal structures . As a consequence of the decreased dermal thickness, adipose tissue may be found just below the epidermis. An increase in papillary dermal blood vessels may also be seen.

Differential diagnosis

The distinctive cutaneous and extracutaneous findings of Goltz syndrome, especially dermal atrophy/fat “herniations” and osteopathia striata, distinguish it from other X-linked dominant genodermatoses. Examples of such conditions include MIDAS (which does not involve the distal extremities), Conradi–Hünermann–Happle, and oral–facial–digital type 1 syndromes. Although an inflammatory component is occasionally observed, the skin lesions of Goltz syndrome are relatively static compared to the evolving lesions of IP.

Treatment

Treatment is supportive, with appropriate subspecialist referral based on the associated abnormalities. The telangiectasias may be improved by pulsed dye laser treatment. Troublesome exophytic papillomas can be treated with curettage or photodynamic therapy.